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PubMed1988

Role of H-2 and non-H-2 genes in control of bacterial clearance from the spleen in Salmonella typhimurium-infected mice.

The ability of mice to clear Salmonella typhimurium from their spleens in the late phase of infection was studied after inoculation with a temperature-sensitive mutant. Clearance of bacteria was delayed in C57BL/6 mice compared with BALB/c, C3H/HeJ, DBA/2, A/J, and CBA mice. The responses of F1 hybrids, backcrosses, and recombinant inbred strains derived from C57BL/6 and BALB/c (both Itys) and of H-2 congenic mice were analyzed. The results showed that the low rate of bacterial clearance was recessive, that the rate of clearance was under polygenic control, and that an H-2-linked gene(s) plays a major role. Among H-2 congenic mice with a C57BL/10 background, three phenotypes of bacterial clearance could be distinguished: high (H-2j, H-2q, and H-2u), intermediate (H-2d, H-2f, H-2k, H-2p, H-2r, H-2s, and H-2v), and low (H-2b) rates. The effect of the H-2 complex was apparent with different genetic backgrounds (Itys and Ityr). In recombinant inbred strains derived from C57BL/6 (Itys) and A/J (Ityr) mice, the effect of the H-2b haplotype on bacterial clearance appeared to be fully expressed only in strains carrying the Itys allele.

Alleles↗
PubMed2003

p21Cip1 nullizygosity increases tumor metastasis in irradiated mice.

p21(Cip1) is a cyclin-dependent kinase inhibitor whose abundance increases in cells exposed to radiation or other DNA-damaging agents. Such increases activate a G1 checkpoint, which allows time for DNA repair before S phase entry. By inhibiting cell cycle progression, p21(Cip1) potentially suppresses tumorigenesis, and in support, we show that p21(Cip1) heterozygous and nullizygous mice develop more tumors than do wild-type mice when exposed to a single dose of gamma-irradiation. Importantly, we also show that p21(Cip1) nullizygosity increases the incidence of metastatic tumors in irradiated mice. We suggest that p21(Cip1) is haploinsufficient for tumor suppression and functions as an antimetastatic agent.

Animals↗
PubMed2005

Multipoint linkage disequilibrium mapping using case-control designs.

Case-control study has been and continues to be one of the most popular designs in epidemiology. More recently, this design has been adopted to test for candidate genes when searching for disease genetic etiology. In this report, we present a multipoint linkage disequilibrium (LD) mapping approach with the focus on estimating the location of the target trait locus. It builds upon a representation, which shows that the difference between a case and a control in probabilities of carrying the target allele of a marker is proportional to that of the trait locus and that the proportionality factor is simply a measure of LD between the trait locus and the marker. Our method has the desired properties that (1) there is no need to specify phases of genotypic data with multiple markers, (2) it provides an estimate of location of the disease locus along with sampling uncertainty to help investigators to narrow chromosomal regions, and (3) a single test statistic is provided to test for LD in the framed region rather than testing the hypothesis one marker at a time. Our simulation work suggests that the proposed method performs well in terms of bias and coverage probability. Extension of the proposed method to account for confounding and genetic heterogeneity is discussed. We apply the proposed method to a published case-control data set for cystic fibrosis.

Alleles↗
PubMed2006

Phosphodiesterase genes are associated with susceptibility to major depression and antidepressant treatment response.

Cyclic nucleotide phosphodiesterases (PDEs) constitute a family of enzymes that degrade cAMP and cGMP. Intracellular cyclic nucleotide levels increase in response to extracellular stimulation by hormones, neurotransmitters, or growth factors and are down-regulated through hydrolysis catalyzed by PDEs, which are therefore candidate therapeutic targets. cAMP is a second messenger implicated in learning, memory, and mood, and cGMP modulates nervous system processes that are controlled by the nitric oxide (NO)/cGMP pathway. To investigate an association between genes encoding PDEs and susceptibility to major depressive disorder (MDD), we genotyped SNPs in 21 genes of this superfamily in 284 depressed Mexican Americans who participated in a prospective, double-blind, pharmacogenetic study of antidepressant response, and 331 matched controls. Polymorphisms in PDE9A and PDE11A were found to be associated with the diagnosis of MDD. Our data are also suggestive of the association between SNPs in other PDE genes and MDD. Remission on antidepressants was significantly associated with polymorphisms in PDE1A and PDE11A. Thus, we found significant associations with both the diagnosis of MDD and remission in response to antidepressants with SNPs in the PDE11A gene. We show here that PDE11A haplotype GAACC is significantly associated with MDD. We conclude that PDE11A has a role in the pathophysiology of MDD. This study identifies a potential CNS role for the PDE11 family. The hypothesis that drugs affecting PDE function, particularly cGMP-related PDEs, represent a treatment strategy for major depression should therefore be tested.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1997

Fabry disease: molecular carrier detection and prenatal diagnosis by analysis of closely linked polymorphisms at Xq22.1.

Fabry disease is an X-linked recessive inborn error of glycosphingolipid catabolism that results from the deficient activity of the lysosomal enzyme alpha-galactosidase A (alpha-Gal A). A rapid, reliable, and universal linkage method was developed for molecular carrier detection and prenatal diagnosis. By determining the informativeness and phase of amplifiable intragenic RFLPs (NcoI and SacI), flanking RFLPs (DXS94 and DXS17), and flanking microsatellite polymorphisms at Xq22.1 (DXS458, DXS454, DXS7424, DXS178, and DXS101), accurate carrier detection, and/or prenatal diagnosis was accomplished in three prototypic, unrelated Fabry families. All linkage diagnoses were confirmed by identification and analysis of the specific alpha-Gal A lesion in each family. Thus, molecular carrier detection and prenatal diagnoses can be performed rapidly and reliably by linkage analysis with intragenic and closely-linked polymorphisms at Xq22.1 in Fabry families whose specific alpha-Gal A lesions have not been determined.

Amino Acid Sequence↗
PubMed1983

Application of bone marrow transplantation in leukaemia and aplastic anaemia.

Marrow transplantation is effective treatment for a number of haematological diseases in patients under the age of 50 who have an HLA-identical sibling donor. It is generally successful when used early in the treatment of aplastic anaemia. It is the only treatment that offers long-term disease-free survival for patients with acute leukaemia who have relapsed at least once, with 10-30 per cent apparent cures. Although still somewhat controversial, it appears also to be the treatment of choice for patients with acute non-lymphoblastic leukaemia in first chemotherapy induced remission and for those with chronic myelogenous leukaemia in the chronic phase since approximately 50-60 per cent of these patients are surviving after marrow transplantation in complete remission, apparently cured. Marrow grafting is the only effective treatment for many patients with inherited immunological-deficiency diseases and certain genetic storage diseases. It is being explored for the therapy of patients with lymphoma, Hodgkin's disease, multiple myeloma, small-cell lung cancer, testicular cancer, ovarian cancer and genetic disorders of haematopoiesis. Cures of congenital Fanconi anaemia, Blackfan-Diamond anaemia, osteopetrosis, and paroxysmal nocturnal haemoglobinuria have been achieved by marrow grafting. Genetic disorders associated with haemolytic anaemia and cyclic neutropenia have been cured by marrow grafting in animals. Target disorders for marrow transplantation in humans are thalassaemia major and sickle cell disease, and, indeed, a first successful transplant for treatment of thalassaemia major has recently been described (Thomas et al, 1982). Marrow transplantation has been limited by the fact that many patients do not have HLA-identical siblings and very few have monozygotic twins. The Seattle team has now explored the use of less well-matched family member donors in more than 80 patients with leukaemia. These donors share one HLA haplotype genetically with the patient and are phenotypically identical at two of the three major HLA loci on the other HLA haplotype (Clift et al, 1979). Overall, the post-transplant survival appears more a reflection of the type and stage of the leukaemia than of the marrow donor. Patients with leukaemia grafted in relapse have a projected survival of 20-30 per cent and those transplanted in remission of 50 per cent. The incidence and severity of GVHD may not be significantly different from that of patients given HLA-identical sibling marrow grafts.(ABSTRACT TRUNCATED AT 400 WORDS)

Acute Disease↗
PubMedDate not supplied

Feline adult beta-globin polymorphism reflected in restriction fragment length patterns.

Adult domestic cats (Felis catus) appear to have the most polymorphic beta-globin system of any species. Reversed-phase high-performance liquid chromatography (RP-HPLC) revealed one alpha-chain and six different beta-globin chains. Each cat may have one to four different beta-globins, and a total of 17 different beta-globin patterns were identified. Based on family studies, a beta-globin gene region with two linked beta-globin gene loci and two to five alleles was proposed. In order to further define the molecular basis of this polymorphism we performed Southern blot analysis of the beta-globin gene region from 25 cats with 13 different HPLC patterns. Genomic DNA was digested with five restriction endonucleases (BamHI, BglII, EcoRI, HindIII, and PstI) and blots were hybridized with a human beta-globin probe. Restriction fragment length polymorphisms (RFLPs) with one to five fragments of 2.2-23 kb in size were found with BglII, EcoRI, HindIII, and PstI. Cats with specific HPLC beta-globin patterns had a unique DNA restriction pattern. The similarly sized BamHI and HindIII fragments of 4.6 kb suggest the presence of two closely linked genes. Furthermore, family studies suggest an autosomal codominant mode of inheritance of the beta-globin chains with seven haplotypes. Thus the RFLP data analyzed in the context of the HPLC haplotypes provide evidence at the DNA level for a feline beta-globin gene region with two closely linked gene loci and two to five alleles.

Animals↗
PubMed1993

Inhibition of Langerhans cell antigen-presenting function by IL-10. A role for IL-10 in induction of tolerance.

IL-10 is a product of activated keratinocytes and is released during the induction phase of contact sensitivity. As IL-10 effects have been described as being mediated by APC, we investigated effects of IL-10 on epidermal Langerhans cells (LC), the resident APC in the epidermis. Initial studies failed to demonstrate effects of IL-10 on MHC class II Ag expression by LC or anti-CD3 mAb- or alloantigen-induced LC-dependent T cell proliferation. However, production of IFN-gamma and IL-2, (but not IL-6) was markedly reduced in these assays. When the soluble-protein Ag specific T cell clones AE7 (Th1) and D10.G4 (Th2) were substituted for unprimed T cells, differential effects of IL-10 on T-cell proliferation were observed. Whereas IL-10-pretreated and untreated LC supported Th2 cell proliferation equally well, IL-10-pretreated LC were essentially unable to induce Th1 cell proliferation in response to native protein or peptide Ag. The inhibitory influence of IL-10 on Th1 cells was observed when fresh or 1 day cultured LC were used; 2- or 3-day cultured LC were affected to a much lesser extent by IL-10 pretreatment. Further, coculture experiments using IL-10-pretreated or untreated LC of a different haplotype suggest that IL-10 negatively regulates a costimulatory signal required for induction of Th1 cell proliferation. To assess whether T cells incubated with Ag and IL-10-pretreated LC were responsive to further stimulation, T cells were rescued after 1 day of coculture with IL-10-pretreated LC and restimulated, either immediately or after 1 to 5 days of rest, with untreated LC in the presence of Ag. T cells incubated with IL-10-pretreated LC were found to be anergic, whereas T cells incubated with untreated LC proliferated normally after further stimulation. However, anergic T cells responded vigorously to IL-2. These data indicate that although IL-10-pretreated LC are effective APC for Th2 cells, they fail to induce Th1 cell proliferation and rather induce clonal anergy in these cells.

Animals↗
PubMed2005

Gene expression and genotyping studies implicate the interleukin 7 receptor in the pathogenesis of primary progressive multiple sclerosis.

Multiple sclerosis (MS) is an enigmatic disease of the central nervous system resulting in sclerotic plaques with the pathological hallmarks of demyelination and axonal damage, which can be directly or indirectly orchestrated by cells from the peripheral circulation. The majority of patients with MS follow a relapsing-remitting course in the early stages of the disease (RRMS) but most ultimately enter a secondary progressive phase (SPMS). About 10% of patients follow a primary progressive course from the onset (PPMS). We measured gene expression in whole blood of people with and without chronic progressive MS (CPMS), PPMS and SPMS, to discover genes which may be differentially expressed in peripheral blood in active disease, and so identify pathologically significant genes and pathways; and we investigated genetic differences in the promoters of dysregulated genes encoded in genomic regions associated with MS. If SPMS and PPMS were independently compared to the controls, there was little overlap in the set of most dysregulated genes. Ribosomal protein genes, whose expression is usually associated with cell proliferation and activation, were dramatically over-represented in the set of most down-regulated genes in PPMS compared to SPMS (P < 10(-4), chi(2)). The T cell proliferation gene IL7R (CD127) was also underexpressed in PPMS, but was up-regulated in SPMS compared to the controls. One interleukin 7 receptor (IL7R) promoter single nucleotide polymorphism (SNP), -504 C, was undertransmitted in PPMS trios (P = 0.05, TDT), and carriers of this allele were under-represented in PPMS cases from two independent patient cohorts (combined P = 0.006, FE). The four known IL7R promoter haplotypes were shown to have similar expression levels in healthy controls, but not in CPMS (P < 0.01, t test). These data support the hypothesis that PPMS has significant pathogenetic differences from SPMS, and that IL7R may be a useful therapeutic target in PPMS.

Down-Regulation↗
PubMed2001

Postglacial colonization of Northern Europe by distinct phylogeographic lineages of the bullhead, Cottus gobio.

Three major phylogeographic lineages of the cottid fish Cottus gobio (bullhead) were identified in northern Europe from mitochondrial DNA sequences and allozyme data. The largely separate freshwater distributions of the lineages demonstrate distinct postglacial colonization histories. West of the Baltic Sea, Swedish lakes were invaded from the southwest (Germany). Another, eastern lineage has colonized the inland waters northeast and east of the Baltic, from refugia in northwest Russia; this lineage comprises a distinct subgroup found only from Estonia. The third lineage, found south and southeast of the Baltic, probably descended from rivers draining to the Black Sea from the north (e.g. Dnepr). In coastal waters of the Baltic Sea, and in near-coast inland waters, the lineages are now found intermixed in various combinations. The alternating fresh- and saltwater phases of the Baltic basin have variously enabled and disabled the use of coastal waters as colonization routes. Hypotheses on the chronology of dispersal and lineage mixing can be based on the distribution of the marker genes and the paleohydrographical record. The diversity of the Fennoscandian bullhead thus comprises anciently diverged (probably mid-Pleistocene) refugial lineages that in their freshwater range constitute distinct evolutionarily significant units. The thorough mixing of the various genomic origins in and around the Baltic, however, refutes the controversial view of distinct species status for the western and eastern ('Cottus koshewnikowi') bullheads. The postglacial contact of the lineages has created new diversity that cannot be interpreted in a conventional hierarchical framework of taxonomic or conservation units.

Animals↗
PubMed1990

Late onset adrenal hyperplasia in a group of Irish females who presented with hirsutism, irregular menses and/or cystic acne.

The aims of this study were to determine the frequency of late-onset adrenal hyperplasia due specifically to 21-hydroxylase deficiency in a group of Irish women who presented at a Dublin Clinic with symptoms of hyperandrogenism, including hirsutism, menstrual irregularities and/or cystic acne, and to determine if those with 21-hydroxylase deficiency showed particular HLA associations. 119 women had blood samples taken basally and 1 h after an injection of 0.25 mg synacthen with the following hormones profiled: 17-hydroxyprogesterone, 11-deoxycortisol, androstenedione, testosterone, DHEAS and cortisol. Blood sampling was carried out between 0900 and 1000 h during the early follicular phase of the menstrual cycle (when applicable). Ninety-six subjects were new referrals to the Clinic for investigation of hyperandrogenism and 23 were acting as controls. In this study, 6% of patients showed evidence of partial 21-hydroxylase deficiency. In addition, 3 of the 6 with partial 21-hydroxylase deficiency had normal baseline levels of 17-hydroxyprogesterone, with the biochemical abnormality becoming manifest only on synacthen stimulation. Late-onset adrenal hyperplasia due to partial deficiency of this enzyme should always be considered as a possible diagnosis in women who present with symptoms of hyperandrogenism. Synacthen stimulation is an important diagnostic tool in elucidating partial enzyme deficiency as baseline 17-hydroxyprogesterone may be normal in such patients.

Acne Vulgaris↗
PubMed1999

Recurrence of Marfan syndrome as a result of parental germ-line mosaicism for an FBN1 mutation.

Mutations in the FBN1 gene cause Marfan syndrome (MFS), a dominantly inherited connective tissue disease. Almost all the identified FBN1mutations have been family specific, and the rate of new mutations is high. We report here a de novo FBN1mutation that was identified in two sisters with MFS born to clinically unaffected parents. The paternity and maternity were unequivocally confirmed by genotyping. Although one of the parents had to be an obligatory carrier for the mutation, we could not detect the mutation in the leukocyte DNA of either parent. To identify which parent was a mosaic for the mutation we analyzed several tissues from both parents, with a quantitative and sensitive solid-phase minisequencing method. The mutation was not, however, detectable in any of the analyzed tissues. Although the mutation could not be identified in a sperm sample from the father or in samples of multiple tissue from the mother, we concluded that the mother was the likely mosaic parent and that the mutation must have occurred during the early development of her germ-line cells. Mosaicism confined to germ-line cells has rarely been reported, and this report of mosaicism for the FBN1 mutation in MFS represents an important case, in light of the evaluation of the recurrence risk in genetic counseling of families with MFS.

Adult↗
PubMed2006

Adrenergic receptor polymorphisms associated with resting heart rate: the HyperGEN Study.

The association between polymorphisms in the beta1, beta2 and alpha2B adrenergic receptor (ADR) genes (ADRB1, ADRB2 and ADRA2B) and resting heart rate was examined in white and African-American participants of the HyperGEN Study. All analyses were adjusted for age, sex, body mass index, alcohol use, smoking status and daily exercise within strata of race, hypertension status and beta-blocker use. The Ser49Gly polymorphism of the beta1 ADR was associated with resting heart rate in hypertensive African-Americans and hypertensive whites taking beta-blockers, with carriers of the Gly allele having a higher mean resting heart rate by 2.7 and 4.4 beats per minute (bpm), respectively. The Arg389Gly polymorphism of the beta1 ADR was associated with lower heart rate in the normotensive African-American sample. A beta1 haplotype (Ser49Gly-Arg389Gly) was modestly associated with resting heart rate in the hypertensive African-Americans. The alpha2B C/A polymorphism was associated with heart rate in hypertensive whites, and both whites and African-Americans taking beta-blockers, with carriers of the A allele having a higher mean resting heart rate. In summary, each of the ADR gene polymorphisms was associated with heart rate in at least one stratum studied, but there was no consistent association from which one would infer a large genetic contribution to heart rate.

Adrenergic beta-Antagonists↗
PubMed2004

Analysis of common IL-6 promoter SNP variants and the AnTn tract in humans and primates and effects on plasma IL-6 levels following coronary artery bypass graft surgery.

Interleukin-6 (IL-6) is a pro-inflammatory cytokine and major mediator of the acute phase response. Single nucleotide polymorphisms within the 5' flanking region (-597G>A, -572G>C and -174G>C) have previously been associated with increased risk of coronary heart disease and influencing transcription of IL-6 both in vitro and in vivo. In addition to these, a polymorphic AnTn tract is also present in the promoter of IL-6. Analysis in five different primate species demonstrated a G allele at -597, -572 and -174 in all species. By contrast, the AnTn tract was polymorphic in at least three species, and was roughly conserved in overall length despite an increase in the relative proportion of A versus T in the evolution of the human sequence from that in the ancestor of the great apes. The effect of the AnTn polymorphism on IL-6 levels was examined following coronary artery bypass graft surgery (CABG), a known inflammatory stimulus for IL-6 production. One hundred and thirty-two patients undergoing CABG were genotyped for the AnTn tract by automated sequencing. Four alleles were identified: A8T12 (allele frequency 0.35, 95% CI 0.29-0.40); A9T11 (0.26, 0.21-0.31); A10T11 (0.21, 0.16-0.26); and A10T10 (0.18, 0.14-0.23). Isolation of the effect of different alleles of the AnTn tract on an identical haplotypic background for the other polymorphisms in the promoter showed that individuals homozygous for A9T11 had significantly higher post-operative IL-6 levels than A10T11 homozygotes (275 +/- 46 pg/ml versus 152 +/- 29; P=0.04). The effect of the A8T12 allele could not be determined separately due to strong allelic association with -174C. The conserved length of the AnTn tract and the association in vivo with IL-6 levels strongly suggest the functionality of the tract on IL-6 expression, independent of contributions from other polymorphic sites within the promoter.

Animals↗
PubMed2000

Extent and distribution of linkage disequilibrium in three genomic regions.

The positional cloning of genes underlying common complex diseases relies on the identification of linkage disequilibrium (LD) between genetic markers and disease. We have examined 127 polymorphisms in three genomic regions in a sample of 575 chromosomes from unrelated individuals of British ancestry. To establish phase, 800 individuals were genotyped in 160 families. The fine structure of LD was found to be highly irregular. Forty-five percent of the variation in disequilibrium measures could be explained by physical distance. Additional factors, such as allele frequency, type of polymorphism, and genomic location, explained <5% of the variation. Nevertheless, disequilibrium was occasionally detectable at 500 kb and was present for over one-half of marker pairs separated by <50 kb. Although these findings are encouraging for the prospects of a genomewide LD map, they suggest caution in interpreting localization due to allelic association.

Computer Simulation↗
PubMed2001

Responses to ultraviolet-B in cell lines from hereditary melanoma kindreds.

Ultraviolet-B (UV-B) triggers a cascade of events involving cell cycle control genes leading ultimately to DNA repair or apoptosis. The hypothesis examined here is that the genetic abnormality predisposing to melanoma affects the ability of the cell to respond appropriately to UV-B, so favouring mutagenesis. Epstein-Barr virus-transformed lymphoblastoid cell lines from hereditary melanoma kindreds were irradiated with UV-B, and changes in p53, p21 and Bcl-2 expression and cell cycle phase distribution were analysed. Twenty-two cell lines were tested: 12 carriers of melanoma susceptibility and 10 non-carriers (unaffected first degree relatives). At 24 h after irradiation with 50 J/m2, 15 of the 22 cell lines showed a rise in G2/M. After 400 J/m2, all the cell lines showed a reduction or loss of G2/M and 17 of the 22 showed an S phase delay. More carriers than noncarriers of melanoma susceptibility showed significant S phase delay after 50 J/m2 (seven out of 12 carriers versus two out of 10 non-carriers). Six of the 10 pairs (carrier versus non-carrier) tested showed discordant cell cycle responses; however the nature of the difference was not universal. Bcl-2 reduction was seen 4 h post-irradiation in all the carriers and non-carriers. The p53 and p21 responses, although showing some individual variations, were not related to carrier status. These results show individual variations in response to UV-B irradiation among cell lines from the members of hereditary melanoma kindreds, but no consistent differences between carriers and non-carriers of melanoma susceptibility.

Apoptosis↗
PubMed2006

Role of CYP pharmacogenetics and drug-drug interactions in the efficacy and safety of atypical and other antipsychotic agents.

Cytochrome P450 (CYP) drug oxidases play a pivotal role in the elimination of antipsychotic agents, and therefore influence the toxicity and efficacy of these drugs. Factors that affect CYP function and expression have a major impact on treatment outcomes with antipsychotic agents. In particular, aspects of CYP pharmacogenetics, and the processes of CYP induction and inhibition all influence in-vivo rates of drug elimination. Certain CYPs that mediate the oxidation of antipsychotic drugs exhibit genetic variants that may influence in-vivo activity. Thus, single nucleotide polymorphisms (SNPs) in CYP genes have been shown to encode enzymes that have decreased drug oxidation capacity. Additionally, psychopharmacotherapy has the potential for drug-drug inhibitory interactions involving CYPs, as well as drug-mediated CYP induction. Literature evidence supports a role for CYP1A2 in the clearance of the atypical antipsychotics clozapine and olanzapine; CYP1A2 is inducible by certain drugs and environmental chemicals. Recent studies have suggested that specific CYP1A2 variants possessing individual SNPs, and possibly also SNP combinations (haplotypes), in the 5'-regulatory regions may respond differently to inducing chemicals. CYP2D6 is an important catalyst of the oxidation of chlorpromazine, thioridazine, risperidone and haloperidol. Certain CYP2D6 allelic variants that encode enzymes with decreased drug oxidation capacity are more common in particular ethnic groups, which may lead to adverse effects with standard doses of psychoactive drugs. Thus, genotyping may be useful for dose optimization with certain psychoactive drugs that are substrates for CYP2D6. However, genotyping for inducible CYPs is unlikely to be sufficient to direct therapy with all antipsychotic agents. In-vivo CYP phenotyping with cocktails of drug substrates may assist at the commencement of therapy, but this approach could be complicated by pharmacokinetic interactions if applied when an antipsychotic drug regimen is ongoing.

Animals↗
PubMed1999

Reference values of urinary excretion of cystine and dibasic aminoacids: classification of patients with cystinuria in the Valencian Community, Spain.

OBJECTIVE: Cystinuria is an autosomal-recessive disorder of the kidneys and small intestine affecting a luminal transport mechanism shared by cystine, ornithine, arginine, and lysine. Three different types of cystinuria can be distinguished according to the excretion of these amino acids in urine samples. We propose cutoff values from our population as references and we present a classification of cystinuric patients using quantitative amino acid chromatography in first morning urine samples. DESIGN AND METHODS: A random sample of forty healthy subjects belonging to general population of the Valencian Community were selected as control subjects. Cystine, lysine, arginine, and ornithine were quantified by reverse-phase HPLC. Seventy-two subjects, diagnosed previously as cystinuric by the cyanide-nitroprusside test were classified. Probands excreting more than 113.12 micromol cystine per mmol of creatinine (i.e., 1,000 micromol cystine per gram of creatinine) were classified as homozygotes. Parents of homozygotes in whom excretion of amino acids were normal were classified as heterozygotes type I. Those probands showing the excretion of at least one amino acid and the sum of urinary cystine plus the basic amino acids higher than the corresponding references ranges in our population were classified as heterozygotes type II or type III (heterozygotes non-type 1). RESULTS: We identified 24 homozygotes, 39 non-type I heterozygotes and 3 type I heterozygotes. The remaining 6 probands could not be classified. Means for cystine, lysine, arginine ornithine and their sum in homozygotes and heterozygotes non-type I were significantly (p < 0.001) in excess of the respective reference ranges. Moreover, means values in homozygotes were statistically different (p < 0.001) from heterozygotes non-type I. CONCLUSION: Urinary excretion of cystine per mmol creatinine allow us to distinguish heterozygotes from homozygotes. However, the best discriminator to distinguish non-type I heterozygotes from normal population might be the excretion of lysine per mmol creatinine. Additional studies including characterization of appropriate haplotypes should be carried out for a more precise identification of types of cystinuria.

Adolescent↗